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Binder selection is a crucial step in continuous twin-screw wet granulation (TSWG), as the material experiences a much shorter residence time (2-40 s) in the granulator barrel compared to batch-wise granulation processes. Polyvinyl alcohol (PVA) 4-88 was identified as an effective binder during TSWG, but the potential of other PVA grades-differing in polymerization and hydrolysis degree-has not yet been studied. Therefore, the aim of the current study was to evaluate the potential of different PVA grades as a binder during TSWG. The breakage and drying behavior during the fluidized bed drying of drug-loaded granules containing the PVA grades was also studied. Three PVA grades (4-88, 18-88, and 40-88) were characterized and their attributes were compared to previously investigated binders by Vandevivere et al. through principal component analysis. Three binder clusters could be distinguished according to their attributes, whereby each cluster contained a PVA grade and a previously investigated binder. PVA 4-88 was the most effective binder of the PVA grades for both a good water-soluble and water-insoluble formulation. This could be attributed to its high total surface energy, low viscosity, good wettability of hydrophilic and hydrophobic surfaces, and good wettability by water of the binder. Compared to the previously investigated binders, all PVA grades were more effective in the water-insoluble formulation, as they yielded strong granules (friability below 30%) at lower L/S-ratios. This was linked to the high dispersive surface energy of the high-energy sites on the surface of PVA grades and their low surface tension. During fluidized bed drying, PVA grades proved suitable binders, as the acetaminophen (APAP) granules were dried within a short time due to the low L/S-ratio, at which high-quality granules could be produced. In addition, no attrition occurred, and strong tablets were obtained. Based on this study, PVA could be the preferred binder during twin screw granulation due to its high binder effectiveness at a low L/S-ratio, allowing efficient downstream processing. However, process robustness must be controlled by the included excipients, as PVA grades are operating in a narrow L/S-ratio range.

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Powder feeding is of critical importance for continuous manufacturing (CM) since next to in-process segregation it is the phenomenon primarily responsible for fluctuations in content uniformity and for content deviations in the final drug product. So far, feeding studies have focused on the characterization of specific feeders and the prediction of their performance for various materials. This work presents a more holistic approach, an early general assessment of the "feedability" of raw materials. With that regard, we established a workflow to: i) predict potential feeding issues, such as the flow stagnation in the hopper based on both the material attributes and the feeder's geometry; and ii) predict the feed rate space using various feeder/screw combinations for powders with an acceptable risk of hopper flow stagnation. Statistical models were developed for this twofold approach using a dataset comprising nine powders and four different feeders. In order to include different feeding equipment into the statistical models, novel equipment descriptors (capturing the effect of different geometries) and performance indicators (the end fill level as indicator for the risk of powder flow stagnation) were introduced. The application of the workflow was demonstrated for a simple formulation, and model validation was successfully performed for an additional powder that was not contained in the original dataset. Finally, the most relevant material attributes were identified, and reduced material characterization data sets were investigated in terms of effects on the model's prediction performance. The workflow presents a promising tool for initial process assessment in early-phase development.

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Typically, smooth lactose particles are used as carrier in dry powder formulations for inhalation. Two classical approaches to improve their aerodynamic behaviour are the addition of fines (milled lactose) or magnesium stearate (MgSt). Mannitol (Parteck® M DPI) as an alternative carrier was used in this study. It has an irregular particle size distribution and a large and rough surface. This could be challenging for the detachment of micronised drug upon inhalation and it is unclear whether classic strategies for the optimisation of aerodynamic performance can be applied. In contrast, its rough surface could be an advantage in terms of drug load. To address these questions, the mannitol carrier was blended with two different drugs using various concentrations up to 50%. Self-produced mannitol fines and MgSt in different amounts and in combination were added. Blends were investigated regarding their in vitro aerodynamic performance, dosing behaviour and powder rheology. An addition of up to 30% drug load was possible while retaining good flowability and constant dosing behaviour. Despite the rough and indented carrier surface of the mannitol carrier, the addition of fines or MgSt increased the inhalable fraction, but higher concentrations of fines, as used for lactose blends, were necessary.

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In dry powder inhalation (DPI), larger carrier particles, typically lactose, are blended with micronised active pharmaceutical ingredient (API) particles to improve handling, processability and inhalable fraction. Alternative carrier materials were researched for years, but did not enter the market yet. In this study, a common lactose carrier for DPI formulations and a spray granulated mannitol carrier were compared to evaluate if the particle engineered mannitol can be considered a serious alternative. Blends with five different API concentrations (0.1 to 4%) were prepared with two APIs. Physical carrier and blend characterisation regarding particle size, morphology, density, shear cell testing and dosing behaviour were performed. Aerodynamic assessment was done using two different inhaler devices (one capsule-based inhaler and one reservoir-based inhaler). In addition, the influence of different flow rates was examined. Results indicated that uniform dosing in metered mass and delivered dose over this API concentration range was achieved due to good flowability of the blends. Furthermore, linear dose delivery could be seen over the added API concentrations. Impaction analysis showed that the respirable fractions of mannitol blends were comparable (for salbutamol sulphate blends) or higher (for budesonide blends) than with a standard lactose carrier.

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Poly (vinyl alcohol) microneedles were fabricated, characterized, and applied to enhance in vitro transdermal delivery of doxorubicin. The microneedles were fabricated using the micromolding technique with the drug load in different locations within the needle array. The polymer solution was assessed for rheological properties, drug dissolution, and chemical structurestudies. Microneedles (unloaded) and drug-loaded microneedles were characterized by optical microscopy, fluorescent microscopy, scanning electron microscopy, and drug release kinetics. Successful microporation of dermatomed human cadaver skin was demonstrated by dye binding, pore uniformity, histology, confocal laser microscopy, and skin integrity studies. The microneedles-mediated transdermal delivery of doxorubicin was investigated using vertical Franz diffusion cells. The fabricated microneedles were sharp, strong, and uniform. In vitro permeation studies showed that the microneedle-treated skin (4351.55 ±â€¯560.87 ng/sq.cm) provided a significantly greater drug permeability than the untreated group (0.00 ±â€¯0.00 ng/sq.cm, n = 4, p < 0.01). The drug location within the needle array was found to affect the drug release profile as well as its permeation into and across human skin. Skin microporation achieved by poly (vinyl alcohol) microneedles was found to enhance transdermal delivery of doxorubicin in vitro.

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OBJECTIVES: Mesoporous silica-based dosage forms offer the potential for improving the absorption of poorly soluble drugs after oral administration. In this investigation, fenofibrate was used as a model drug to study the ability of monomodal ('PSP A') and bimodal ('PSP B') porous silica to improve release by a 'spring' effect in in vitro biorelevant dissolution tests. Also investigated was the addition of various polymers to provide a 'parachute' effect, that is, to keep the drug in solution after its release. KEY FINDINGS: Loading fenofibrate onto PSP A or PSP B porous silica substantially improved the dissolution profile of fenofibrate under fasted state conditions compared with both pure drug and the marketed product, TriCor® 145 mg. Adding a polymer such as hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone or copovidon (HPMCAS, PVP or PVPVA) sustains the higher release of fenofibrate from the PSP A silica, resulting in a combination 'spring and parachute' effect - loading the drug onto the silica causes a 'spring' effect while the polymer enhances the spring effect (HPMCAS, PVP) and adds a sustaining 'parachute'. Interestingly, a silica to polymer ratio of 4:1 w/w appears to have an optimal effect for fenofibrate (HPMCAS, PVP). Dissolution results under conditions simulating the fasted state in the small intestine with the PSP A or the PSP B silica with HPMCAS added in a 4:1 w/w ratio show very substantial improvement over the marketed, nanosized product (TriCor® 145 mg). CONCLUSIONS: Further experiments to determine whether the highly positive effects on fenofibrate release observed with the silica prototypes investigated to date can be translated to further poorly soluble drugs and to what extent they translate into improved in-vivo performance are warranted.

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1.Tenencia de la tierra y la situación de los bosques tropicales en Bolivia: zonas ecológicas y población en Bolivia, legislación sobre tenencia de la tierra y aprovechamiento de los recursos naturales hasta los años 90, el movimiento indígena, territorios indígenas, ley de servicio nacional de reforma agraria, titulación de los territorios indígenas 2.Los chiquitanos de Lomerio: ubicación geográfica de la zona de Lomerio, breve historia de los chiquitanos, población y lengua, servicios basicos cultura 3.El proyecto forestal Lomerio: origen y estructura del proyecto, el plan de manejo, la partiipación de las comunides, el aserradero La Esperanza, sello verde para Lomerio, Aspectos políticos